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bioRxiv · 10.1101/2023.05.09.540046

Host genetic background regulates the capacity for anti-tumor antibody-dependent phagocytosis

Glassbrook, J. E.·Hackett, J. B.·Muniz, M. C.·Bross, M.·Dyson, G.·Movahhedin, N.·Ullrich, A.·Gibson, H. M.
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Abstract

BackgroundAntitumor antibody, or targeted immunotherapy, has revolutionized cancer treatment and markedly improved patient outcomes. A prime example is the monoclonal antibody (mAb) trastuzumab, which targets human epidermal growth factor receptor 2 (HER2). However, like many targeted immunotherapies, only a subset of patients benefit from trastuzumab long-term. In addition to tumor-intrinsic factors, we hypothesize that host genetics may influence subsequent immune activation. MethodsTo model the human population, we produced F1 crosses of genetically heterogeneous Diversity Outbred (DO) mice with BALB/c mice (DOCF1). Distinct DOCF1 mice were orthotopically implanted with the BALB/c-syngeneic TUBO mammary tumor line, which expresses the HER2 ortholog rat neu. Treatment with anti-neu mAb clone 7.16.4 began once tumors reached [~]200 mm3. Genetic linkage and quantitative trait locus (QTL) effects analyses in R/qtl2 identified loci associated with tumor growth rates. Locus validation was performed with BALB/c F1 crosses with recombinant-inbred Collaborative Cross (CC) strains selected for therapy-associated driver genetics (CCxCF1). The respective roles of natural killer (NK) cells and macrophages were investigated by selective depletion in vivo. Ex vivo macrophage antibody-dependent phagocytosis (ADCP) assays were evaluated by confocal microscopy using 7.16.4-opsonized E2Crimson-expressing TUBO tumor cells. ResultsWe observed a divergent response to anti-tumor antibody therapy in DOCF1 mice. Genetic linkage analysis detected a locus on chromosome 10 that correlates to a robust response to therapy, which was validated in CCxCF1 models. Single-cell RNA sequencing of tumors from responder and non-responder models identified key differences in tumor immune infiltrate composition, particularly within macrophage (M{varphi}) subsets. This is further supported by ex vivo analysis showing M{varphi} ADCP capacity correlates to in vivo treatment outcomes in both DOCF1 and CCxCF1 models. ConclusionsHost genetics play a key regulatory role in targeted immunotherapy outcomes, and putative causal genes are identified in murine chromosome 10 which may govern M{varphi} function during ADCP.

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Glassbrook, J. E., Hackett, J. B., Muniz, M. C., Bross, M., Dyson, G., Movahhedin, N., Ullrich, A., Gibson, H. M.. 2023-05-09. Host genetic background regulates the capacity for anti-tumor antibody-dependent phagocytosis. https://doi.org/10.1101/2023.05.09.540046

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